Inherited immunodeficiencies associated with proximal and distal defects in T cell receptor signaling and co-signaling

T lymphocytes are central cells of adaptive immunity. Activation of T lymphocytes by the antigen receptor of T cells (TCR) and co-stimulatory molecules involve specific signaling components and cascades. Those are essential for development, differentiation and effector responses of T lymphocytes. Over the last three decades, identification of primary immunodeficiencies associated with defects in development and activation of T lymphocytes provided new and unexpected insights into TCR signaling and co-signalling and their relation with protective immunity in humans. Mutations in components of the proximal and distal TCR signaling like the TCR-CD3 complex, protein tyrosine kinases and phosphatases, adaptor proteins, second messengers like Ca(2+) mobilization and the MAPK kinase and nuclear factor kappa B (NFκB) pathways impede T cell development and functions, causing immunodeficiency and immune dysregulation manifestations such as autoimmunity and inflammation. Mutations that impair co-signaling delivers by co-stimulatory molecules of the tumor necrosis factor (TNF), the CD28 and the signaling lymphocytic activation molecule (SLAM) receptor families, have no effect or slight impact on T-cell development but impair T cell responses such as expansion. Interestingly, these latter are often associated with infectious susceptibility restricted to particular pathogens like Epstein-Barr virus (EBV) and human papillomavirus (HPV), highlighting the molecular “specialization” of co-stimulatory molecules to shape TCR-dependent T cell responses to specific pathogens or infected cells.